Prostate cancer is the most frequently diagnosed cancer among men in the United States. Yet, the vast majority of men with prostate cancer will not die from their disease, reflecting the clinically-indolent behavior of their tumors. Indeed, most clinicians now agree that prostate cancer is both over-diagnosed and over-treated, a situation exacerbated by widespread prostate specific antigen (PSA) screening, and leading to significant treatment-associated morbidity. A key clinical question then is which men with prostate cancer could be spared unnecessary and potentially harmful therapy. Addressing this question requires a more detailed molecular understanding of clinically-indolent prostate cancer. In prior published studies, we identified three previously unrecognized molecular subtypes of prostate cancer based on distinct patterns of gene expression. Notably, one of these subtypes, subtype-1 , exhibited clinically-favorable behavior, and we speculate might represent a class of indolent tumors not requiring therapeutic intervention. Our more recent studies using array-based comparative genomic hybridization (array CGH) now indicate a distinct genetic basis underlying the different subtypes, including specific deletion within chromosome cytobands 5q21 and 6q15 in the clinically-favorable subtype-1 tumors. These findings at once implicate novel tumor suppressor genes (TSGs) in the pathogenesis of clinically-favorable prostate cancer, and define their location. The goal of our proposed research is to discover the pathogenic TSGs at 5q21 and 6q15 underlying a clinically-favorable prostate cancer subtype. The specific aims are (1) To delimit the boundaries of recurrent deletion at 5q21 and 6q15 by array CGH;and (2) To screen remaining candidate TSGs for DNA mutations and promoter hypermethylation. These studies will further our knowledge of the molecular pathogenesis of prostate cancer. Our findings may also suggest novel gene-based markers for the diagnosis of clinically- favorable tumors, leading to improved treatment stratification and clinical management of men with prostate cancer. PROJECT NARRATIVE: The proposed studies aim to identify the cancer genes underlying a clinically-favorable subtype of prostate cancer. Our findings will further our understanding of the pathogenesis of prostate cancer, and may suggest novel gene-based markers for an improved classification of prostate tumors and management of patients with prostate cancer.